1. Field of the Invention
The present invention provides a process for the preparation of stable, crystalline salts of a cephalosporin intermediate which are substantially free of the .DELTA..sup.2 isomer and are convertible into broad-spectrum cephalosporin antibiotics.
2. Background Art
A large number of cephalosporin antibiotics are known and are widely used in the treatment of bacterial infection. The semi-synthetic antibiotic cefepime is a useful broad-spectrum antibiotic which is described by Aburaki, et al, in U.S. Pat. No. 4,406,899, issued Sep. 27, 1983 and by Kaplan, et al, in U.S. Pat. No. 4,910,301, issued Mar. 20, 1990 which is represented by the formula ##STR2##
A preferred process for the preparation of the antibiotic cefepime comprises the 7-acylation of a stable, crystalline compound of the formula ##STR3## wherein X is HI, HCl or H.sub.2 SO.sub.4 and which are substantially free of the .DELTA..sup.2 isomer. These crystalline cephalosporin intermediates are disclosed by Brundidge, et al, in U.S. Pat. No. 4,714,760, issued Dec. 22, 1987 and by Aburaki, et al, in U.S. Pat. No. 4,659,812, issued Apr. 21, 1987.
In U.S. Pat. No. 4,868,294, issued Sep. 19, 1989, Brundidge et al. describe the preparation of stable, crystalline 7-amino-3-[(1-methyl-1-pyrrolidinio)methyl] ceph-3-em-4-carboxylate salts substantially free of the .DELTA..sup.2 isomer starting from 7-amino cephalosporanic acid (7-ACA) in 1,1,2-trichlorotrifluoroethane (Freon TF) or 1,1,1-trichlorotrifluoroethane as the solvent.
However, by international agreement under the Montreal Protocol on Substances That Deplete the Ozone Layer and the subsequent 1990 London amendment, the international community agreed to curb and ban the production of chlorofluorocarbons (CFCs) by the end of the century. Recently, under terms of the 1990 Clean Air Act, the United States has moved up the deadline to cease production of CFCs and other ozone-depleting chemicals, including Freon TF, to the end of 1995.
The preparation of intermediates of Formula I substantially free of the .DELTA..sup.2 isomer is advantageously carried out as described in U.S. Pat. No. 4,868,294 in Freon TF as the solvent. By international agreement and United States law, the production of Freon TF will be phased out and Freon TF will be banned from commercial use. Thus, there is an urgent need to find a suitable solvent replacement for Freon TF in the preparation of intermediates of Formula I. The replacement solvent must meet certain criteria such as solubility of reactants, reaction rates, ratios of reactants, high yields and, more importantly, the elimination of the undesirable .DELTA..sup.2 isomer. Consequently the criteria for the process to produce the intermediates of Formula I severely restricts the selection of a solvent. The unique characteristics of Freon TF and, its isomer, as the solvent in the process for the preparation of intermediates of the Formula I are described by D. Walker et al. in the Journal of Organic Chemistry, Vol. 53, 1988, pages 983-991. On page 985, D. Walker et al. state that Freon TF and, its isomer, were the only two solvents which provided the best yields while minimizing in situ formation of the undesirable .DELTA..sup.2 isomer. In view of the teachings of the art, it was unexpected and surprising that the present inventors discovered that a series of cycloalkanes would substitute for the chlorofluorocarbons, Freon TF and its isomer, in the process for the preparation of intermediates of the Formula I starting from 7-ACA.